Support is requested for a Keystone Symposia meeting entitled Mechanisms of HIV Persistence: Implications for a Cure, organized by Olivier Lambotte, Steven G. Deeks and Guido Silvestri. The meeting will be held in Boston, Massachusetts from April 26 - May 1, 2015. Despite long-term control of HIV replication with combination antiretroviral therapy, HIV persists as silenced integrated DNA in memory CD4 T cells, and possibly in other cellular reservoirs, including nave cells and macrophages. Low level replenishment of the reservoir via limited cycles of replication, may also contribute to persistence, at least in some patients. Curing HIV infection will only occur if these barriers are reversed, or if host capacity to control HIV indefinitely is improved. A number of promising interventions which might reverse latent infection have been identified, and proof that such drugs affect HIV transcription in vivo provided in pilot clinical trials. The observation that few patients treated during primary infection control durably replication-competent HIV after interrupting therapy suggests host responses might be manipulated, leading to a functional cure. The path forward will require a detailed understanding of the mechanisms of viral latency which could lead to theidentification of new drugs, and a better knowledge of the plasticity and dynamics of the main HIV cell reservoirs: CD4 T cells and macrophages. Furthermore, the role of the tissue microenvironment has to be investigated with the major help of non-human primate models. At the 2015 Keystone Symposia meeting on Mechanisms of HIV Persistence: Implications for a Cure, experts from both within and outside the HIV field will present findings from recent advances on immune mechanisms and therapeutic strategies which could lead to HIV cure. The topic of this meeting is highly relevant to the DAIDS mission to increase basic knowledge of the pathogenesis and transmission of HIV.